EP2636676A2 - Cristallisation dýépidaunorubicine x HCI - Google Patents
Cristallisation dýépidaunorubicine x HCI Download PDFInfo
- Publication number
- EP2636676A2 EP2636676A2 EP13002444.1A EP13002444A EP2636676A2 EP 2636676 A2 EP2636676 A2 EP 2636676A2 EP 13002444 A EP13002444 A EP 13002444A EP 2636676 A2 EP2636676 A2 EP 2636676A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- solvent
- epidaunorubicin hydrochloride
- volume
- mixture
- hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- STQGQHZAVUOBTE-RPDDNNBZSA-N (7s,9s)-9-acetyl-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 STQGQHZAVUOBTE-RPDDNNBZSA-N 0.000 title claims abstract description 98
- 238000002425 crystallisation Methods 0.000 title description 5
- 230000008025 crystallization Effects 0.000 title description 5
- 239000002904 solvent Substances 0.000 claims abstract description 156
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 107
- 239000000203 mixture Substances 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 31
- 150000001298 alcohols Chemical class 0.000 claims abstract description 22
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 239000011877 solvent mixture Substances 0.000 claims description 46
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 24
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 229940045799 anthracyclines and related substance Drugs 0.000 claims description 9
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical group O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims description 8
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 229960001904 epirubicin Drugs 0.000 claims description 8
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims 2
- 239000013078 crystal Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 8
- 125000000524 functional group Chemical group 0.000 description 7
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- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
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- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical class CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 2
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 2
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 2
- 229960004176 aclarubicin Drugs 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical compound BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 0.000 description 2
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 2
- 229930188550 carminomycin Natural products 0.000 description 2
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 2
- 229950001725 carubicin Drugs 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- -1 for example Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 229960001221 pirarubicin Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- 239000013598 vector Substances 0.000 description 2
- 229960000641 zorubicin Drugs 0.000 description 2
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 2
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7s,9s)-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 description 1
- QVLAWKAXOMEXPM-UHFFFAOYSA-N 1,1,1,2-tetrachloroethane Chemical class ClCC(Cl)(Cl)Cl QVLAWKAXOMEXPM-UHFFFAOYSA-N 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical class CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
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- 150000001721 carbon Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
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- 229910052593 corundum Inorganic materials 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000011143 downstream manufacturing Methods 0.000 description 1
- 229960003265 epirubicin hydrochloride Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
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- 102000004169 proteins and genes Human genes 0.000 description 1
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- 229910001845 yogo sapphire Inorganic materials 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to crystalline epidaunorubicin hydrochloride and a process for the production thereof.
- Anthracyclines comprise a large group of naturally occurring bioactive compounds. Several anthracyclines are used in clinics as anticancer chemotherapeutic drugs. Examples of clinically important substances are daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, aclarubicin, carminomycin and zorubicin. Anthracyclines can be either produced by chemical synthesis or by fermenting microorganisms.
- anthracyclines are used as such (for example, aclarubicin, daunorubicin and carminomycin) or are semi-synthetic derivatives of other anthracyclines (such as epirubicin, idarubicin, doxorubicin, pirarubicin and zorubicin).
- Anthracyclines are effective against leukemia and various solid cancerous tumors. Worldwide most used anthracyclines are doxorubicin and epirubicin. Epidaurorubicin is the key-intermediate in the synthesis of epirubicin.
- epidaunorubicin hydrochloride amorphous precipitation thereof from a solution by addition of an antisolvent.
- a basic solution of epidaunorubicin is treated with methanolic hydrochloric acid to adjust the pH value in a range between 2 and 5, and subsequently epidaunorubicin hydrochloride is precipitated by addition of an ether.
- Amorphous precipitation of epidaunorubicin hydrochloride has the drawback that the precipitated epidaunorubicin hydrochloride is only purely soluble and often purified unsatisfactorily.
- the problem to be solved by the present invention is the provision of a simple process for the purification and crystallization of epidaunorubicin hydrochloride which allows for epidaunorubicin hydrochloride to be crystallized in a form in which it is stable and readily soluble.
- the method of the present invention makes use of epidaunorubicin hydrochloride as a starting material.
- epidaunorubicin hydrochloride can be used which is produced from precursors in a preceding chemical synthesis.
- commercially available epidaunorubicin hydrochloride can be used which is to be further purified.
- epidaunorubicin hydrochloride which is produced by use of suitable microorganisms and converted into the corresponding hydrochloride in a subsequent step.
- Epidaunorubicin hydrochloride is crystallized in a solvent system comprising solvents A, B and C which differ from each other. Therefore, the solvent system referred to herein comprises at least three different kinds of solvents.
- Solvent A is selected to have the capability to dissolve epidaunorubicin hydrochloride.
- solvent A is selected from the group consisting of C1 and C2 halogenated solvents and mixtures thereof.
- Solvent A can be a single solvent or a mixture of solvents, but is preferably a single solvent.
- every kind of solvent can be used as long as it has one or two carbon atoms, comprises at least one halogen atom and is suitable to dissolve epidaunorubicin hydrochloride.
- solvent A contains 1 - 3 and more preferably 2 or 3 halogen atoms.
- halogens chlorine and bromine are preferred.
- the halogen atoms can be the same or different.
- solvent A can be a compound which has at least one chlorine atom and/or at least one bromine atom. It is preferred that the halogen atom(s) present in solvent A is a (are) chlorine atom(s).
- the compound or compounds used as solvent A can contain further functional groups in addition to the halogen atom(s). On the other hand, it may be preferred that solvent A does not contain such further functional group(s).
- solvent A is a saturated compound and thus does not contain a double bond. It can furthermore be preferred that solvent A has only one carbon atom.
- solvent A is selected from the group consisting of, dichloromethane, dibromomethane, chloroform, bromoform, dichloroethanes (such as 1,1-dichloroethane or 1,2-dichloroethane), dibromo-ethanes (such as 1,2-dibromoethane), trichloroethanes (such as 1,1,1-trichloroethane or 1,1,2-trichloroethane), tetrachloroethanes (such as 1,1,2,2-tetrachloroethane) and mixtures thereof. More preferably, solvent A is selected from chloroform, dichloromethane and mixtures thereof.
- Solvent B is selected on its ability to purify epidaunorubicin hydrochloride from common impurities. It is selected from the group consisting of C1 - C5 straight and branched alcohols and mixtures thereof. Solvent B can be a single solvent or a mixture of solvents, but is preferably a single solvent. Every alcohol having a C1 - C5 carbon skeleton can be used as solvent B as long as it is able to allow for purification of epidaunorubicin hydrochloride. In particular, solvent B can be a monoalcohol or a polyalcohol. Furthermore, solvent B includes alcohols having further functional groups in addition to the hydroxyl group(s). It may be preferred, however, that solvent B has no further functional groups.
- solvent B is a saturated compound and therefore does not contain double or triple bonds.
- solvent B is selected from the group consisting of C1 - C3 straight and branched alcohols and mixtures thereof.
- solvent B is selected from the group consisting of C1 straight and branched alcohols, C2 straight and branched alcohols, C3 straight alcohols and mixtures thereof.
- solvent B is selected from the group consisting of methanol, ethanol, 1-propanol and mixtures thereof.
- Solvent C is selected to be an antisolvent to epidaunorubicin hydrochloride. It is selected from the group consisting of C1 - C5 straight and branched alcohols and mixtures thereof. Solvent C can be a single solvent or a mixture of solvents, but is preferably a single solvent. Solvent C is also selected to provide lower solubility to epidaunorubicin hydrochloride than solvent B. In this context, it is submitted that it is within the expert knowledge of a person skilled in the art, to identify from the alcohols described herein as solvent C those alcohols which provide lower solubility to epidaunorubin hydrochloride than solvent B.
- the skilled person may dissolve epidaunorubin hydrochloride in a solvent selected from the group consisting of C1 - C5 straight and branched alcohols and mixtures thereof, and determine the dissolution capacity of this solvent for epidaunorubin hydrochloride.
- the skilled person may dissolve epidaunorubin hydrochloride in a different solvent selected from the group consisting of C1 - C5 straight and branched alcohols and mixtures thereof, and determine the dissolution capacity of this solvent for epidaunorubin hydrochloride. From the two kinds of solvents examined, the skilled person designates as solvent B the alcohol(s) in which the solubility of epidaunorubin hydrochloride is higher.
- solvent C the alcohol(s) in which the solubility of epidaunorubin hydrochloride is lower.
- every alcohol having a C1 - C5 carbon skeleton can be used as solvent C as long as it is able to act as an antisolvent to epidaunorubicin hydrochloride.
- solvent C can be a monoalcohol or a polyalcohol.
- solvent C includes alcohols having further functional groups in addition to the hydroxyl group(s). It may be preferred, however, that solvent B has no further functional groups.
- solvent C is a saturated compound and therefore does not contain double or triple bonds.
- solvent C is selected from the group consisting of C3 - C5 straight and branched alcohols and mixtures thereof. According to a further preferred embodiment, solvent C is selected from the group consisting of C3 branched alcohols, C4 straight and branched alcohols, C5 straight and branched alcohols, and mixtures thereof. Most preferably, solvent C is selected from the group consisting of isopropanol, 1-butanol, 2-butanol and 1-pentanol.
- the solvent system of the present invention comprises 0.1 - 20 % by volume of solvent A, 7 - 50 % by volume of solvent B and 45 - 92 % by volume of solvent C.
- the solvent system comprises 1 - 6 % by volume of solvent A, 10 - 40 % by volume of solvent B and 54 - 89 % by volume of solvent C.
- the solvent system is devoid of solvents other than solvents A, B or C. According to this embodiment, the solution does not contain solvents apart from solvents A, B and C. However, the solvent system is allowed to contain, apart from epidaunorubicin hydrochloride, other ingredients, such as for example, salts.
- the solvent system consists of epidaunorubicin hydrochloride, and solvents A, B and C. In this case, no further ingredients are allowed to be present in the solvent system.
- the process of the present invention is preferably performed by dissolving epidaunorubicin hydrochloride in a solvent mixture I and, subsequently, contacting the resulting solution of epidaunorubicin hydrochloride with a solvent mixture II.
- Solvent mixture I is characterized in comprising solvent A and having the capability to dissolve epidaunorubicin hydrochloride. Solvent mixture I is also allowed to consist only of solvent A. In this case, however, solvent mixture II must comprise solvents B and C. Nevertheless, it is preferred that solvent mixture I comprises, in addition to solvent A, also solvent B or solvent C, or a mixture of solvents B and C. In this case, it is preferred that solvent mixture I comprises (i) solvent A, on the one hand, and (ii) solvent B or C or a mixture thereof, on the other hand, in a volume ratio between 1 : 2 and 4:1. Preferably, the volume ratio between (i) solvent A and (ii) solvent B, C or a mixture thereof, is between 0,75 : 1 and 3:1, and most preferably between 1 : 1 and 2:1.
- Solvent mixture II comprises solvent C.
- Solvent system II is generally allowed to consist only of solvent C. In this case, however, solvent mixture I has to comprise solvent A and solvent B. According to a preferred embodiment, solvent mixture II comprises solvents B and C.
- Solvent mixture I is able to dissolve epidaunorubicin hydrochloride. Accordingly, in a first step of the process of the present invention, epidaunorubicin hydrochloride is dissolved completely in solvent mixture I. If necessary, one can assist in dissolving epidaunorubicin hydrochloride in solvent mixture I by increasing the temperature of solvent mixture I. For example, dissolution of epidaunorubicin hydrochloride in solvent mixture I can be performed at a temperature in the range between 40 - 80°C, preferably between 50 - 70°C, and most preferably between 55 and 65°C. Preferably, heating of solvent mixture I is accompanied by stirring.
- solvent mixture II can be added to the solution of epidaunorubicin hydrochloride in solvent mixture I.
- solvent mixture II it is also possible to add the solution of epidaunorubicin hydrochloride in solvent mixture I to solvent mixture II.
- the solvent mixtures can be brought into contact by every conceivable means. For example, it is possible to drop, inject or pour the epidaunorubicin hydrochloride-containing solvent mixture I in solvent mixture II or vice versa.
- the solvent mixtures are brought into contact by slowly dropping the epidaunorubicin hydrochloride-containing solvent mixture I in solvent mixture II or vice versa. Dropping can be performed, for example, for a period of 1 second to 1 hour, such as 1 minute to 40 minutes, or 5 minutes to 30 minutes.
- the resulting solvent system upon contact of the solution of epidaunorubicin hydrochloride in solvent mixture I with solvent mixture II, the resulting solvent system comprises 0.1 - 20 % by volume, preferably 0.1 - 15 % by volume, more preferably 0.1 - 12 % by volume, and most preferably 0.1 - 10 % by volume, of solvent A.
- solubility of epidaunorubicin hydrochloride is reduced.
- concentration of solvent A in the solvent system decreases below 20 % by volume, preferably below 15 % by volume, more preferably below 12 % by volume, and most preferably below 10 % by volume, crystallization of epidaunorubicin hydrochloride is initiated under suitable conditions. In this context, however, it has been found that decreasing the concentration of solvent A below a certain level is not sufficient to cause crystallization. It is essential that the solvent(s) used for diluting solvent A and thus to reduce the concentration of solvent A in the solvent mixture is (are) suitable solvent(s).
- the concentration of epidaunorubicin hydrochloride in the solvent system is adjusted to be between 7 g/l and 30 g/l, preferably between 7.5 g/l and 25 g/l, and most preferably between 8 g/l and 20 g/l.
- the pH value of the epidaunorubicin hydrochloride-containing solvent system is in a range between pH 2 - 5.
- the resulting mixture is cooled to a temperature in the range between 5 - 35°C, preferably 15 - 30°C, and most preferably 20 - 30°C.
- the resulting mixture is cooled to a temperature in the range between 5 - 35°C, preferably 15 - 30°C and most preferably 20 - 30°C, within a period of 2 - 8, preferably 3 - 7 and more preferably 4 - 6 hours, starting from the time of contact of solvent mixture I with solvent mixture II.
- the resulting mixture is stirred at a temperature in the range between 5 - 35°C, preferably 15 - 30°C and most preferably 20 - 30°C, for a period of 2 - 24 hours, preferably 4 - 20 h, more preferably 8 - 16 hours, even more preferably 10 - 14 hours.
- Crystalline epidanunorubicin hydrochloride obtained by carrying out the process of the present invention preferably has the powder X-ray diffraction pattern as defined in table 1.
- the powder X-ray diffraction pattern is preferably measured using K ⁇ 1 radiation; the STOE STADI P POWDER DIFFRACTION SYSTEM (Stoe CIE GmbH, Darmstadt, Germany) is preferably used as the measuring device.
- Table 1 Powder X-ray diffraction pattern of epidaunorubicin hydrochloride crystals according to a preferred embodiment of the present invention.
- Crystalline epidanorubicin hydrochloride of the present invention more preferably has the powder X-ray diffraction pattern as defined in table 2.
- the data of table 2 are preferably obtained with the STOE STADI P POWDER DIFFRACTION SYSTEM (Stoe CIE GmbH, Darmstadt, Germany) using K ⁇ 1 radiation:
- Table 2 More preferred powder X-ray diffraction pattern of epidaunorubicin hydrochloride crystals as obtained in accordance with the present invention.
- crystalline epidaunorubicin hydrochloride of the present invention has one or more of the powder X-ray diffraction values (particular range of relative intensity at a particular diffraction angle 2(theta)) outlined in table 3 as preferably measured with the STOE STADI P POWDER DIFFRACTION SYSTEM (Stoe CIE GmbH, Darmstadt, Germany) using K ⁇ 1 radiation: Table 3: Powder X-ray diffraction pattern of epidaunorubicin hydrochloride crystals according to an even more preferred embodiment of the present invention.
- Crystalline epidaunorubicin hydrochloride produced according to the process described herein can have the physical parameters as shown in table 4. These data were obtained in single X-ray analysis using an instrument from Xcalibur Oxford Diffraction and MoKa (0,7107 mm -1 ) as radiation source. Table 4: Data of single X-ray analysis of epidaunorubicin hydrochloride as obtained in accordance with the present invention.
- the process of the present invention allows for the production of crystalline epidaunorubicin hydrochloride having high purity, improved solubility in methanol and high thermal stability.
- the crystalline epidaunorubicin hydrochloride produced according to the process of the present invention has monoclinic crystal structure.
- the crystal is described by vectors of unequal length, as in the orthorhombic system. They form a rectangular prism with a parallelogram at its base. Hence two pairs of vectors are perpendicular, while the third pair makes an angle other than 90°.
- the present invention provides crystalline epidaunorubicin hydrochloride having a monoclinic phase content of at least 10 %.
- the monoclinic phase content of the crystalline epidaunorubicin hydrochloride is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99%.
- the crystalline epidaunorubicin hydrochloride consists only of the monoclinic form. It is further preferred that the crystalline epidaunorubicin hydrochloride of the present invention does not form part of a complex with other molecules, for example, such as DNA, RNA or proteins.
- the crystalline epidaunorubicin hydrochloride of the present invention excels in purity and shows improved solubility, in particular, in methanol. Therefore, it can be beneficially used in downstream processes for the production of anthracyclines.
- crystalline epidaunorubicin hydrochloride can be used to produce epirubicin.
- the process for producing epirubicin from epidaunorubicin hydrochloride as a starting material is well-known in the art. Because of its high purity and good solubility in methanol, the use of crystalline epidaunorubicin hydrochloride as a starting material for the synthesis of epirubicin is beneficial over the use of amorphous epidaunorubicin hydrochloride.
- the mixture was cooled to room temperature within a period of 5 hours, and subsequently stirred for 12 h at room temperature.
- the resulting crystals were separated from the solvent mixture by means of filtration, washed with 50 ml tert-butyl-methylether and dried at vacuum ( ⁇ 400 mbar).
- the crystals were analyzed and confirmed as epidaunorubicin hydrochloride.
- the yield was 9.2 g, the purity was 98.2 %.
- the mixture was cooled to room temperature within a period of 5 hours, and subsequently stirred for 12 h at room temperature.
- the resulting crystals were separated from the solvent mixture by means of filtration, washed with 50 ml tert-butyl-methylether and dried at vacuum ( ⁇ 400 mbar).
- the crystals were analyzed and confirmed as epidaunorubicin hydrochloride.
- the yield was 9.2 g, the purity was 98.2 %.
- the mixture was cooled to room temperature within a period of 5 hours, and subsequently stirred for 12 h at room temperature.
- the resulting crystals were separated from the solvent mixture by means of filtration, washed with 50 ml tert-butyl-methylether and dried at vacuum ( ⁇ 400 mbar).
- the crystals were analyzed and confirmed as epidaunorubicin hydrochloride.
- the yield was 9.1 g, the purity was 98.0 %.
- the mixture was cooled to room temperature within a period of 5 hours, and subsequently stirred for 12 h at room temperature.
- the resulting crystals were separated from the solvent mixture by means of filtration, washed with 50 ml tert-butyl-methylether and dried at vacuum ( ⁇ 400 mbar).
- the crystals were analyzed and confirmed as epidaunorubicin hydrochloride.
- the yield was 9.1 g, the purity was 98.0 %.
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EP2301943B1 (fr) | 2009-09-08 | 2014-01-08 | Heraeus Precious Metals GmbH & Co. KG | Cristallisation d'épidaunorubicine x HCI |
DE102011103751A1 (de) * | 2011-05-31 | 2012-12-06 | Heraeus Precious Metals Gmbh & Co. Kg | Kristallisierung von Epirubicinhydrochlorid |
KR101428340B1 (ko) * | 2012-12-31 | 2014-08-07 | 현대자동차주식회사 | 이온성 용매를 이용한 락타이드 제조법 |
WO2015149001A1 (fr) | 2014-03-27 | 2015-10-01 | The Brigham And Women's Hospital, Inc. | Conjugués de médicaments activés métaboliquement pour vaincre la résistance dans une thérapie du cancer |
DE102014208194A1 (de) | 2014-04-30 | 2015-11-05 | Heraeus Deutschland GmbH & Co. KG | Aufreinigung von Epidaunorubicin |
US10301343B2 (en) | 2015-03-30 | 2019-05-28 | Meiji Seika Pharma Co., Ltd. | Method of producing epirubicin and novel production intermediate thereof |
CN109384822B (zh) * | 2017-08-11 | 2021-08-03 | 鲁南制药集团股份有限公司 | 一种盐酸表柔比星晶型及其制备方法 |
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JPS6442498A (en) * | 1987-08-07 | 1989-02-14 | Biogal Gyogyszergyar | Improvement for collecting daunorubicin hydrochloride from fermentation liquid |
DK1034181T3 (da) * | 1997-11-28 | 2006-03-20 | Dainippon Sumitomo Pharma Co | Krystallinsk amrubicinhydrochlorid |
ATE488524T1 (de) * | 1997-12-05 | 2010-12-15 | Mercian Corp | Kristallines anthracyclin antibiotikum und seine herstellung |
AU750738B2 (en) * | 1998-10-16 | 2002-07-25 | Microbiopharm Japan Co., Ltd. | Crystallization of doxorubicin hydrochloride |
US7485707B2 (en) * | 2003-07-02 | 2009-02-03 | Solux Corporation | Thermally stable crystalline epirubicin hydrochloride and method of making the same |
US8802830B2 (en) * | 2005-12-20 | 2014-08-12 | Solux Corporation | Synthesis of epirubicin from 13-dihydrodaunorubicine |
WO2007077562A2 (fr) * | 2006-01-04 | 2007-07-12 | Do-Coop Technologies Ltd. | Compositions antiseptiques et leurs procédés d'utilisation |
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- 2010-09-08 CN CN201080039787.2A patent/CN103347891B/zh active Active
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US4861870A (en) | 1982-12-23 | 1989-08-29 | Farmitalia Carlo Erba S.P.A. | Process for purifying anthracyclinone glycosides by selective adsorption on resins |
US5945518A (en) | 1995-03-22 | 1999-08-31 | Sicor Societa' Italiana Corticosteroida S.p.A. | Process for the preparation of anthracycline antibiotics |
US5874550A (en) | 1996-12-16 | 1999-02-23 | Pharmachemie B.V. | Process for preparing epirubicin or acid addition salts thereof from daunorubicin |
WO2008135195A1 (fr) | 2007-05-08 | 2008-11-13 | W.C. Heraeus Gmbh | Souches génétiquement modifiées produisant des métabolites d'anthracycline utiles en tant que médicaments contre le cancer |
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KR101480376B1 (ko) | 2015-01-09 |
RU2564415C2 (ru) | 2015-09-27 |
EP2301943A1 (fr) | 2011-03-30 |
AU2010294532A1 (en) | 2012-03-08 |
MX2012002869A (es) | 2012-09-07 |
US20140357848A1 (en) | 2014-12-04 |
CA2772260C (fr) | 2015-02-24 |
CN103347891A (zh) | 2013-10-09 |
BR112012005126A2 (pt) | 2017-10-03 |
JP2016094445A (ja) | 2016-05-26 |
WO2011029576A1 (fr) | 2011-03-17 |
UA111580C2 (uk) | 2016-05-25 |
RU2012113549A (ru) | 2013-10-20 |
EP2636676A3 (fr) | 2014-01-01 |
CN103347891B (zh) | 2016-06-01 |
KR20120068023A (ko) | 2012-06-26 |
PL2301943T3 (pl) | 2014-06-30 |
US8822658B2 (en) | 2014-09-02 |
EP2301943B1 (fr) | 2014-01-08 |
US9434756B2 (en) | 2016-09-06 |
US20140148587A1 (en) | 2014-05-29 |
CA2772260A1 (fr) | 2011-03-17 |
ZA201202405B (en) | 2012-12-27 |
BR112012005126A8 (pt) | 2018-02-14 |
SG178461A1 (en) | 2012-03-29 |
US20120232291A1 (en) | 2012-09-13 |
AU2010294532B2 (en) | 2014-04-10 |
JP2013503826A (ja) | 2013-02-04 |
CN105713055A (zh) | 2016-06-29 |
HRP20140263T1 (hr) | 2014-04-25 |
JP5858481B2 (ja) | 2016-02-10 |
US8686164B2 (en) | 2014-04-01 |
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